ON THE REACTIONS OF THE FORMAMIDINES. VI. SOME THIAZOLE

Publication Date: September 1916. ACS Legacy Archive. Note: In lieu of an abstract, this is the article's first page. Click to increase image size Fre...
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ON

THE REACTIONS OF THE FORMAMIDINES. VI.

1841

The degree of dissociation of chloralethylalcoholate into its constituents has been determined in benzene for a wide range of concentrations, and in bromoform, ethylene bromide, and nitrobenzene in fewer concentrations. It is dissociated in dilute solutions, associated in more concentrated ones. There appears to be no relation between the degree of dissociation and the dielectric constant of the solvent. We take pleasure in acknowledging our indebtedness to the Warren Fund of the American Academy of Arts and Sciences for the excellent polarimeter and spectroscope which were placed a t our disposal for this work. BRYNMAWR,PA.

[CONTRIBUTION FROM

THE

DEPARTMENT OF CHEMISTRY OF THE UNIVERSITY OF KANSAS.]

ON THE REACTIONS OF THE FORMAMIDINES. VI. SOME THIAZOLE DERIVATIVES. BY F. B. DAINSA N D A. E. STEPHENSON. Received June 24, 1916.

Owing to the inability of one of the authors to continue this investigation, it has been deemed best to publish the results already obtained as a preliminary paper in this special field. It has already been pointed out' that compounds containing a methylene grouping react with ease with the substituted formamidines, giving a primary amine and the complex CHNHR in place of the H2 of the methylene group, as follows: >CH2 RN=CHNHR = >C=CHNHR RNH2 This occurs not only in the malonic ester, acetoacetic ester and benzyl cyanide type, but also with ring compounds like the pyrazolones and isoxazolones. I n the isothiohydantoins (ketotetrahydro-thiazoles), there is found the complex -CO - CH2 - S-,which exhibits the general reactions characteristic of an acid methylene grouping, such as aldehyde, phthalic anhydride, nitroso derivatives, etc. Such compounds should by analogy react with the formamidines ; a supposition confirmed by the following experiments : Diphenyl-isothiohydantoin (2-phenylimido-3-phenyl-4-keto-tetra-hydrothiazole) was readily obtained by heating in alcohol solution thiocarbanilide and chloroacetic acid. Small amounts of phenyl mustard oil glycollide and phenyl thiourethan were also formed. Molar quantities of the isothiohydantoin and diphenylformamidine were heated a t 140-50' for five hours. The reaction product contained Ber., 35, as09 (1902);THISJOURNAL, 31, 1148(19091:35,959, 970 (1913).

+

+

1842

F. B. DAINS

AND A. E. STEPHENSON.

aniline, and, in 78% yield, 2-phenylimido-3-phenyl-4-keto-g-anilidomethylene-tetrahydrothiazole, C6H6N-CO-C = CHNHC6Ha

I

I

CBHSN= C S This crystallizes from alcohol in the form of short, pale yellow needles melting a t 202 '. Calc. for C ~ ~ H I ~ ON, N S11.32%. : Found: 11.50%, 11.31%.

Hydrolysis of the 1sothiohydantoin.-Io g. of the anilidomethylene derivative, 150 cc. alcohol and 15 cc. conc. hydrochloric acid, were heated under a reflux condenser for four hours. The products isolated were (I) diphenyl urea, (2) z,4-diketo-5-anilidomethylene-tetrahydrothiazole (m. p. 192 '), formed by the hydrolysis of the phenylimido group, obtained also, as will be described later, by the condensation of diphenylformamidine due to and the diketothiazole, (3) ~-phenyl-a,4-diketotetrahydrothiazole further loss of the anilidomethylene group, and (4) aniline hydrochloride. The results thus show a progressive hydrolysis of the molecule. It is of especial interest, however, in this fact that in all the investigations of the anilidomethylene derivatives, this is the first instance noted where that grouping could be split off without complete rupture of the entire molecule. Di-o-tolyl-isothiohydantoin was prepared according to the method of Wheeler and Jamieson.' It melts a t 153' and gives a benzal derivative melting a t 182.5 It should be noted here that these benzal substitution products can be formed by the direct heating of the aldehyde and hydantoin without the use of any solvent or condensing agent. Molar quantities of the thiazole and diphenylformamidine, when heated a t 140-50' for three hours gave a 75% yield of ~-o-tolylimido-~-o-tolyl-~keto-5-anilidomethylenetetrahydrothiazole. From alcohol, this crystallizes in pale yellow, silky needles with a melting point of 200-1

'.

'.

Calc. for CzrHllONsS: N, 10.53%.

Found: 10.44%~ 10.65%.

The monosubstituted thiazoles containing a methylene group react in an analogous manner. Thus diphenylformamidine and phenylisothiohydantoin at I 50' yielded almost quantitatively z-phenylimido-4-keto-5-

anilidomethylene-tetrahydrothiazole,HN-CO-C

1

I

= CHNHC6H5

C6HsN = S It is almost insoluble in alcohol, chloroform, gasoline and benzene, soluble in hot glacial acetic acid, pyridine and nitrobenzene. From the latter solvent it crystallizes in lemon yellow needles melting a t 266.5

'.

Calc. for C~~HI~ONS.S: N, 14.24%.

Found:

14.12%,

13.90%.

When phenyl-isothiohydantoic acid, CaH6N = CNHz - S - C H r COOH, is heated a t I ~ C P I ~ O ' with diphenyl formamidine, the same THIS JOURNAL, 25, 369 (1903).

ON THE REACTIONS OF THE FORMAMIDINES.

VI.

1843

anilidomethylenephenylthiazole (m. p. 266 ") is obtained. This involves both ring closure, due doubtless to the high temperature and reaction with the methylene hydrogen. Analogous results were obtained when the same thiohydantoic acid and benzaldehyde were allowed to react a t a temperature of I~o-~o',though for a few moments the thermometer rose to zoo'. The ring was closed and there was formed z-phenylimido4-keto-5-benzaltetrahydrothiazole(m. p. 2 j4'), a substance which had been previously obtained by condensing the aldehyde and thiazole in alcohol solution by means of sodium.' A similar reaction has been noted2 in the case of the acetyl or benzoyl thiohydantoic acid, since when this is heated with benzaldehyde, there is formed I-acyl-z-thio-4-benzalhydantoin. Another type of thiazole containing a substituted amino group, the 2-methylphenylamido-4-keto-tetrahydrothiazole, was found to condense a t I j o ' with diphenyl formamidine yielding the z-methyl-phenylamido4-keto-j -anilidomethylene-tetrahydrothiazole, N(333

;I

co

1

CeII6N - C - S - C = CHNHCaH6

This crystallizes from alcohol in reddish granules melting a t 180'. It is soluble in hydrochloric acid and reprecipitated by alkalies. Calc. for C17H150N3S: N, 13.60%.

Found: 13.50%.

Diketo-thiazoles.-The presence of two keto groups in the ring seems to have little effect, either in diminishing or increasing the reactivity of the methylene hydrogen. Thus 3-phenyl-2,4-diketo-tetrahydrothiazole was heated with diphenylformamidine a t 140-jo O for three hours, giving an 80% yield of 3-phenyl-z ,4-diketo-5-anilidomethylene-tetrahydrothiazole. This is difficultly soluble in alcohol from which it crystallizes in pale yellow glistening leaflets with a melting point of 192-3 '. Calc. for C I ~ H I ~ O ~ NN, Z S9.46%. :

Found: 9.53%, 9.59%.

As has been noted in the early part of this article, this same compound was obtained by the partial hydrolysis of the 2-phenylimido-3-phenylanilidomethylene derivative. While the above was the main reaction product obtained in heating the thiazole and formamidine, there Kas also formed a small amount of a compound, soluble in alcohol, melting a t 237' and containing 13.11% nitrogen. The data corresponds to that demanded for diphenyl urea, which might readily be formed by the action of aniline on the original thiazole. Condensation of a n Unsubstituted Diketothiazo1e.-Under the same conditions as in previous experiments, a molar mixture of diphenyl formami2

Wheeler and Jamieson, THISJOURNAL, 25, 367 (1903). Wheeler, Nicolet and Johnson, Am. Chem. J., 46, 469 (1911).

TREAT B. JOHNSON

I844

AND SIDNEY

E. HADLEY.

dine and the 2,4-diketo-tetrahydrothiazolegave the 2,4-diketo-5-anilidomethylene-tetrahydrothiazole, HN-CO

I

I

OC-S-C CHNHCcHa This is very difficultly soluble in hot alcohol from which it crystallized in almost colorless plates melting a t 233 '. Calc. for C 1 ~ H s O ~ N N, ~ S :12.73%. Found: 12.96%, 13.03%.

As a matter of interest it may be noted here that experiments show that the true thiohydantoins containing a methylene group condense with the formamidines giving substitued amino methylene derivatives of the type, R N - CO

sc

HN-C

I

CHNHCsHr

isomeric with the thiazole derivatives. These investigations are being continued in this laboratory. LAWRENCE, KANSAS.

[CONTRIBUTIONS FROM THE SHEFFIELD CHEMICAL LABORATORY OF YALEUNIVERSITY. ]

RESEARCHES ON PYRIMIDINES. LXXXI. SECONDARY-PYRIMIDINE-NUCLEOSIDES AND THEIR UNIQUE BEHAVIOR ON HYDROLYSIS.' JOHNSON AND SIDNEY E. HADLEY. Received June 28, 1916.

BY TRBATB.

This is the fourth paper from this laboratory on pyrimidine nucleosides and, like those preceding it, deals with the chemistry of uracil and thymine combinations containing alcohol groupings in position 4 of the pyrimidine ring. The classification adopted namely, primary, secondary and tertiary NH

I CO I

- CO 1 CH II

NH - CH (Uracil) (1). MH CO

I CO I

-

I CH II

NH

I

CO

- CO

/

CCHs

I

I/

I

I

NH

I CO I

- CO

I II

CCHs

-

NH - CH (Thymine) (11). NH - CO

C.CH20H NH (111). NH

- CO

'i"r

CO

CH

I

I

I

-

II

CC(CH3)zOH NH - CCH(CH3)OH NH NH - C.CHz0H (IV). (V) (VI). The observations recorded in this paper have developed from an investigation on nucleosides which was originally started in this laboratory by Dr. Lewis H. Chernoff in 1913. The paper has been constructed from a dissertation presented by Mr. Sidney Edward Hadley to the Faculty of the Graduate School of Yale University, 19x6, in candidacy for the Degree of Doctor of Philosophy.

.